This ongoing Program Project Grant was originally initiated in order to develop a team approach to clarifying the mechanisms by which tumor cells affect the skeleton and cause disastrous clinical consequences such as hypercalcemia, bone pain and susceptibility to fracture. During the original project period, we gathered a team with expertise in identifying factors which were involved in disrupting calcium homeostasis and affecting bone metabolism. Recent progress in this field has been dramatic and we now wish to extend our studies on characterization of the effects of the heterogeneous tumor factors which can disturb calcium homeostasis. Since the time of our original application, a number of tumor factors associated with hypercalcemia have been identified, so that it is now possible to characterize fully the effects of these factors not only on bone metabolism in vitro, but also on renal function and calcium homeostasis in vivo. As a consequence, we have gathered a team of investigators with the skills in bone cell biology, protein purification, molecular biology, bone histomorphometry, and renal physiology to accomplish our goals. The specific aims of this application are 1) to identify completely the tumor-associated factors which are responsible for causing hypercalcemia in specific tumors associated with the humoral hypercalcemia of malignancy, breast cancer and in hematologic malignancies such as myeloma, and 2) to determine the effects of these specific tumor-associated peptides (alone and in combination) on calcium homeostasis in vivo, and the relative importance of their specific effects on bone and renal function by our in vitro and in vivo models.